Benjamin P. Levy, MD: Let’s move on to our next section, which is the role of immunotherapy in early stage disease. All of us are aware of the immuno tsunami that has occurred in non–small cell lung cancer, specifically in the advanced-stage setting.

We now have 9 different approvals and different indications for advanced-stage disease without an actionable mutation. It’s incredible to think about how many options are currently available as single-agent I/O [immune-oncology], dual-checkpoint blockade, chemotherapy with I/O, dual checkpoint blockade with 2 cycles of chemotherapy. Of course, all these are approved for advanced-stage disease and lead to improved outcomes.

Similar to the targeted therapy paradigm, we’re trying to look at the role of these strategies in early stage disease. There is a role that we’re starting to learn about for perioperative immunotherapy and immunotherapy combinations. Clearly, 1 of the ways it has been explored first has been in the neoadjuvant setting, and it makes a lot of sense to look at this in the neoadjuvant setting.

Jarushka, you’ve worked a lot on this topic. Talk a little about the biological rationale for immunotherapy in early stage disease, and maybe even the clinical rationale for neoadjuvant immunotherapy.

Jarushka Naidoo, MBBCh: I’d be pleased to talk about that. I obviously worked with Dr Patrick Forde on his neoadjuvant study of nivolumab, and I have my own study that is looking at combining immunotherapy with radiation in the neoadjuvant setting for stage III disease. So I have some understanding as to why these approaches are interesting both clinically and biologically.

Biologically, when we think about how PD-1 or PD-L1 inhibitors work, the idea is that releasing this inhibition allows our immune cells to kill the tumor cells. But this requires antigen presentation by the tumor cells to generate a group of what we call antigen-specific T cells that are able to recognize the tumor.

Therefore, it makes sense to use immunotherapy in the neoadjuvant setting when the tumor mass is already in place. Imagining a large tumor mass with lots of different tumor clones, this presents us with an opportunity for a large volume of potential antigens to be presented and to generate antigen-specific T cells.

From there, the idea is that you generate this compendium of antigen-specific T cells, almost like a cancer encyclopedia. After you’ve had your treatment, these antigen-specific T cells can then act as your means of immunologic memory, so if a tumor clone does rear its ugly head, you have a specific T cell that can come and take that out and act as a silent and constant killer without necessarily needing repeated dosing.

That is something that has been looked at in tumor models comparing neoadjuvant vs adjuvant immunotherapy approaches. Investigators have looked to see if the generation of T cells is different when given pre- or postoperatively. This has certainly been corroborated in multiple different tumor models and different tumor types, not just long cancer. This has also been studied in breast cancer. So from a biological perspective, it makes a lot of sense.

From a clinical perspective, we talked a little about the downsides of giving a neoadjuvant chemotherapy approach. One was the toxicity of chemotherapy that may limit the ability to get to the definitive stage of surgery or incur certain surgical complications.

That’s not the case with immunotherapy. We have been really positive about the improved tolerability of anti–PD-1 and PD-L1 agents. Thus far in the neoadjuvant studies, which I know the rest of the panel will go through in due course, we haven’t seen any unacceptable safety signals in some of these early studies. When Dr Forde and my study were being developed, there was a concern for pneumonitis. That was the highest on our list. Thankfully, we have not seen that as an unacceptable rate of toxicity that has limited the ability to get to surgery.

None of those things appears to be panning out with immunotherapy—the tolerability question, the ability to get to surgery, the complications of surgery. If anything, it seems to be tentatively easier than giving neoadjuvant chemotherapy. So there are many clinical pluses associated with this approach.

Benjamin P. Levy, MD: A beautiful explanation. I’m sold. I’m ready to do it on all my patients. Let’s talk about some definitions that keep coming up on these trials: major pathologic response and complete pathologic response. Dr Naidoo, maybe you can walk us through what these are and how they have correlated with outcome, or if they have at all.

Jarushka Naidoo, MBBCh: With regard to pathologic complete response, way back when all of us treated breast cancer, a long time ago I’m sure, that was the Holy Grail that many patients were going for. Patients were treated with neoadjuvant chemotherapy. For breast cancer, we know that pathologic complete response correlates with survival outcomes. Was this the same or true for neoadjuvant chemotherapy in lung cancer? Unfortunately, the answer is no.

One of the reasons is that the incidence of a pathologic complete response—basically achieving complete tumor eradiation for patients treated with neoadjuvant chemotherapy—was very low. In the major published studies, this ranged for 0% to 16%, with a median of around 4%. Statistically, the incidence of this is too low to really be used as a real-time end point for neoadjuvant chemotherapy and, therefore, presumably other therapies as well. Therefore, it was not selected as a pathologic end point of interest in some of the early studies. Major pathologic response was based on a seminal study published in 2012. I think this was based on 192 surgically resected lung cancer samples from patients who had undergone neoadjuvant chemotherapy. A pathologist looked at all these samples and identified that this end point, major pathologic response—defined as less than 10% viable tumor cells—was significantly associated with overall survival in this compendium of studies.

That was the data for which, for example, Dr Forde’s study in the New England Journal of Medicine used major pathologic response as the pathologic end point of interest. But this was with the understanding that this was based on a clearance of chemotherapy in the setting of, or lack of experience in, neoadjuvant immunotherapy.

Since then we have learned a lot, and the pathologists who were involved in this study and others have really come to the table and try to understand how we could potentially do better from a pathologic end point standpoint.

I would refer you to a great paper in the Annals of Oncology that was published in 2018. In that study, the 20 patients who were treated on the New England Journal of Medicine paper with neoadjuvant nivolumab were assessed very carefully for their pathologic features.

What they identified was that certain pathologic features of the regression bed of the surgically resected specimens harbored specific features that could be combined in a score called the immune-related pathologic response criteria score. This included a number of factors, including immune activation, cell death, tissue repair, and a regression-based score. They were assisted by multiple pathologists and found that it was reproducible.

This has been looked at in a couple of different neoadjuvant settings. It has been looked at not just in lung cancer but also in melanoma and other cancers. It looks to be something that is going to be studied into the future. So there is a lot to be done here. I’m pretty sure it’s not going to be where we end.

Benjamin P. Levy, MD: Yeah. As with everything else, we’re just beginning to scratch the surface of all this. Identifying the right end points takes a lot of scientific, deep work, which you’ve gone over. I’d be curious to see what that end point is at 5, 10 years down the road vs what it is now, and whether these end points will lead to drug approvals.

Transcript Edited for Clarity